Skeletal muscle is repetitively injured throughout life and requires continual regeneration. The ability of skeletal muscle to regenerate declines significantly with age, although the specific factors that govern this decline are poorly understood. One key systemic factor that declines with age in females is the sex hormone, estradiol (E2). We have discovered that experimental manipulation of both E2 levels and that of its receptor ER? specifically in satellite cells of young adult females leads to decrement in satellite cell pool size and decline in regenerative potential. This project seeks to understand the mechanisms by which these effects are mediated in females, probes the sex-specific nature of this regulation, and investigates interventions in aged mice. We will elucidate the molecular and cellular regenerative details mediated by estradiol and importantly the functional outcomes on muscle contraction. Driven by our robust preliminary data, we will test the overarching hypothesis that E2 is the primary sex hormone regulating skeletal muscle maintenance through estrogen receptor-mediated mechanisms in satellite cells. In Aim 1 we design experiments to probe the cellular physiological consequences of the E2-ER? signaling axis in satellite cells. Aim 2 focuses on estrogenic mechanisms regulating satellite cells and muscle regeneration of males, testing the provocative hypothesis that E2 plays a significant role in males as well as females. In Aim 3 we will interrogate responsiveness of satellite cells in aged mice to E2 and a new, third generation selective estrogen receptor modulator, bazedoxifene (BZA), which we have shown to be an estrogen receptor agonist in satellite cells. Within each of the three primary aims we utilize state of the art transcriptional and chromatin profiling approaches to gain insight into signaling pathways, for example, that are similar (or distinct) between satellite cells from females and males when sex hormones or receptors are manipulated. At the completion of this project we will know in molecular detail how E2 contributes to overall skeletal muscle health through hormone receptor mediated-mechanisms specifically in satellite cells. Women spend one-third of their life in an E2-deficient state and androgen (and thus potential estrogenic effects mediated by aromatase) declines in males with age. As the aging population continues to increase it becomes increasingly important that the impact of this biological variable on skeletal muscle health be understood.